Download Medical Genetics: The New

Essays of an Information Scientist, Vol:5, p.222-237, 1981-82
The
Number
Current Contents, #36, p.5-20, September 7, 1981
Medical
Genetics:
New Preventive
Medicine
36
September
Recently,
I published an essay describing the current state of preventive
medicine and the impressive efforts being made by the Centers for Disease
Control (CDC) to incorporate
this philosophy
into
standard
medical
practice. 1 Shortly after that essay was
published,
I received
a letter from
cytogeneticist
D. Soudek,
Kingston
Psychiatric
Hospital,
Kingston,
Ontario, pointing out I had failed to discuss
a very important aspect of preventive
medicine—medical
genetics. z In fact, I
by this imporwas somewhat stunned
tant reminder as I had been planning an
essay on medical genetics for some
time. Considering ISF’s early work in
developing
a citation
index to the
genetics
literature,
it is somewhat
disconcerting
to realize
how little
editorial attention I’ve devoted to any
aspect of genetics. Soudek’s letter merely emphasizes that even knowledgeable
people do not automatically
think of
medical genetics as an important part of
preventive medicine-if
not now, certainly in the future.
Until recently, physician involvement
in what is now being called medical
genetics was largely confined to discussing the recurrence of genetic disorders
and explaining the limited number of
options available
for preventing
the
birth of a child with these disorders.
Since, for many years, most genetic
diseases could only be detected after the
birth of a child, medical genetics was
7,1981
mainly the province of physicians and
researchers
investigating
“esoteric”
diseases known to have a genetic component. One exception to this generalization was the discovery that different
Rh blood groups in parents can pose a
threat to their offspring. Blood tests to
detect this hereditary
incompatibility
have been available for many years.
In the past 20 years, new and more
accurate methods of diagnosing hereditary disease
have been developed.
Researchers
have also recognized that
many diseases that occur later in life are
genetically
influenced.
As a result,
physicians and basic research scientists
alike have increasingly focused their attention on the genetic basis for disease.
In addition, each year thousands of persons are requesting amniocentesis
and
other medical techniques
which can
detect specific diseases in the fetus.
People
are requesting
these
tests
because they have a family history of
hereditary
diseases,
are concerned
about having a defective child, or are
concerned
about having a child with
chromosomal
abnormalities
related to
the parent’s advanced age.
More than 3,000 diseases are known
to have a genetic component,
and 150
new ones are being recognized
each
year, according to James R. McBee, director, National Clearinghouse
for Human Genetic Disease, which pro tides
information
on genetic screening and
treatment programs. J So the preventive
222
value of recognizing the presence of, or
susceptibihty to, genetic disease can be
far-reaching.
Methods
for prenatally
diagnosing
genetic disease have helped to diminish
the fears of people who might not have
chosen to become parents without the
knowledge now available. In a sirnifar
vein, individuals
with a hereditary
susceptibilhy
to certain diseases can
now take steps to moderate the disease
or begin treatment in its early stages.
Whife knowledge of inherited factors
in disease has been available since the
early 1900s, it generally was not applied
to clinical practice until the 1950s.4 Part
of this delay can be attributed
to the
early
affiliations
of some
medical
“hygienists)’q with the already
wellestablished eugenics movement. Scientists in Europe and the US were doing
research on the hereditary transmission
of human traits prior to the twentieth
century,
but institutions
devoted
to
predicting the recurrence
of inherited
human diseases originated in the US and
UK. As is well-known,
in Germany—
where eugenics research and publication were quite active around the turn
of the century-eugenics
became
a
political issue, despite the best intentions of many geneticists.
Two of the major institutions in the
US and UK where genetics was first appfied to human health were also associated with the controversial
field of applied eugenics. The Laboratory
of National Eugenics, established in London
in 190’7, was closely aligned with the
beliefs of its founder, Francis Galton. 5.6
He is well-known for KIS advocacy of
selective human breeding.
Charles B. Davenport,
who established the frst institute
for human
genetics in the US, tried to show that
criminality
and insanity
represented
simple Mendelian traits. 7 The Eugenics
Records Office was founded by Davenport in Cold Spring Harbor, New York,
in 1910.6 This was only ten years after
223
the rediscovery of the work of Gregor
Johann Mendel, the nineteenth-century
monk who elucidated the fwst laws of
heredity.
Mendel theorized
that the
traits observed in pea plants occurred
through generations
because of paired
elementary
units of heredity.
These
were later to be cafled genes. He
worked out the statistical occurrence of
these
traits
and,
although
further
refinements and elaborations to his laws
have been made, they stifl form the
foundation of modem genetics. There is
a considerable
mythology
about the
long delay in the acceptance
of his
ideas.8,g
In the early 1900s, then, human
genetics was often treated as that part of
eugenics “concerned
with the acquisition of knowledge of human heredity.”b
In many cases, this happened because
both subjects were taught by the same
person at universities and cofleges.
Although many geneticists dld not investigate medical genetics because of its
association with eugenics, an even more
important factor was the difficulty of
studying the hereditary transmission of
diseases and traits in humans. As is so
>ften the case, scientists who were interested in human genetics did not have
[he technical methodology to study hereditary disease in man.
While the eugenics movement
and
methodological limitations may explain
~ general lack of interest in medical
;enetics among genetics researchers,
it
ioes not explain why physicians took so
ong to adopt Mendelian thinking into
heir practice and research. The reason
‘or this is the same as for their lack of inerest in preventive medicine. Accordng to A. CapIan, Hastings Center, Has:ings-on-Hudson,
New York, they sim)Iy were not aware of its relevance. Durng the early part of this century, physicians infrequently came across diseases
hat showed Mendelian inheritance patems. And diseases which showed such
)attems were frequently
untreatable.
Consequently,
physicians didn’t believe
they were worth studying. 10Additionally, doctors and researchers were “busily
extending their new etiologic model of
disease,”lo
Medical attention
at this
point was focused on microbial sources
of disease and infection.
As a result of these factors, genetics
remained primarily the territory of zoologists and botanists until the 1950s. At
this point, the control of nongenetic
diseases—those caused by infection and
nutritional deficiency—was
advancing,
so that attention could focus more on
The
number
of
genetic
disease.4
diseases recognized as displaying Mendelian inheritance
patterns also began
to increase.
Medical geneticists
were
now able to make estimates of the risks
of recurrence of hereditary disease.
According to F. Clark Fraser, McGill
University, the next major “boost” to
medical genetics came with advances in
molecular
and biochemical
genetics,
which led to the identification
of “inborn errors of metabolism.”q Thk term
was first introduced
by A,E. Garrod,
Oxfotd University,
who was also the
first to describe Mendelian inheritance
in human disease. II.12The term “inborn
error of metabolism” is now used to describe any genetically determined
biochemical disorder in which enzymatic
defects produce problems of metabolism. The discovery that one such enzyme deficiency, which results in mental retardation (phenylketonuria),
could
be successfully
treated
had major
ramifications.4 Infants in most states of
the US and in the UK are now regularly
screened for th~ defectl J and for congenital hypothyroidisms
During the 1950s, a number of major
discoveries further advanced our understanding of medical genetics. In 1956,
J.H. Tjio,
Experimental
Station
of
Aula, Zaragoza, Spain, and A. Levan,
Institute of Genetics, Lund, Sweden; 14
and C.E. Ford and J.L. Hamerton,
Medical Research Council, Berkshire,
224
England, 15independently demonstrated
that the number of chromosomes
in
man was 46, rather than the 48 previously believed. The methods developed by
these scientists made possible the accurate study of human chromosomes.
They also led to the recognition,
in
1959, that chromosomal
irregularities
are associated with a number of syndromes. ls-1~ Victor McKusick,
Johns
Hopkins University, explains that these
events actually led to the birth of “clinical genetics” in that they “gave the
clinical geneticist ‘his organ’ like the
cardiologist has hk heart, the ophthalmologist his eye and so on. ” He adds
that various biochemical
methods developed since the 1950s, and somatic
cell hybridization,
a technique in which
the genetic information from two different types of cefls is combined,
have
helped researchers further define genetically-based biochemical differences in
humans. 19
At present, physicians and scientists
use tissue culturing and karyotyping to
detect chromosomal
abnormalities.
In
this type of chromosome analysis, cells
are allowed to divide in tissue culture.
They are then arrested in metaphase,
the stage of cell dhision during which
the chromosomes are separated into exactly similar halves. The cells are then
stained and the chromosomes are either
observed under a microscope,
and abnormalities
noted; or, a microphotograph of the chromosomes is taken and
the chromosomes arranged according to
a standard classification system. ‘Ilk arrangement of the chromosomes is called
a karyotype.
The karyotype
is then
studied for structural or numerical irregularities.
A process cafled banding,
in which the patterns of bands on the
chromosomes
are studied, enables scientists to observe, with great precision,
mat erial that maybe present, absent, or
irregularly located on the chromosome.
Incidentally, the word karyotype should
not be confused with eukaryote or pro-
karyote, although these words are all
derived from the Greek “karyo,” which
refers to the nucleus of the cell.~ A prokaryote is an organism—bacteria,
for
example—that
does not have a true
nucleus, so that nuclear material is scattered in the cytoplasm of the cell. A
eukaryote has a true nucleus, bounded
by a nuclear membrane.
More recently, with the development
of diagnostic methods such as amniocentesis, ultrasound, and radiologic examination,
it became possible to diagnose chromosomal
aberrations,
certain
inborn errors of metabolism, and other
congenital abnormalities
in the fetus.
Amniocentesis,zl-~
the most widely
used method of prenatal diagnosis, is a
process in which amniotic fluid is drawn
from the womb during the fourteenth to
sixteenth week of gestation and analyzed for those diseases and chromosomal abnormalities suspected in the fetus. The fluid itself is analyzed for neural tube defects, and cells within the fluid are cultured and anafyzed for many
chromosomal
abnormalities
and more
than 100 inborn errors of metabolism.
The predominant
application of amniocentesis so far has been for detection
of Down syndrome (mongolism) in the
fetuses of women 35 and over. During
this period the risk of giving birth to a
child with a chromosomal
disorder appreciably
escalates.
About 40 other
disorders have been diagnosed through
amniocentesis,
including Tay-Sachs disease, a deficiency of brain lipid metabolism: galac[osemia,
a biochemical deficienc y of carboh ydrate metabolism; and
thalassemia, a hemolytic anemia caused
by abnormal synthesis of hemoglobin. 24
Amniocentesis
is a fairly painless and
safe procedure. Its main risk, if any, is a
less than one half of one percent chance
of inducing abortion. 25
Ultrasound,
another method of prenatal diagnosis, involves the passage of
high frequency
sound
through
the
womb. This enables physicians to locate
the fetus and placenta,zb and is usualy
225
used in conjunction with amniocentesis.
Ultrasound makes it possible to detect
multiple fetuses. By accurately locating
the fetus and placenta,
the physician
can avoid fetal injury when drawing amniotic fluid through a needle. Examination of the fetal head through ultrasound afso can help in the diagnosis of
anencephaly, the absence of a cranium,
and other structural defects.
The most direct way of examining the
fetus is through a fetoscope,
a tube
which can enter the womb and be used
to remove a sample of fetal blood or tissue.27,z~ Disorders such as sickle cell
anemia and thalassemia
can be diagnosed this way. Unfortunately,
the fetoscope, which is still in the research stage
of development,
has an appreciable risk
of fetal Ioss. Z4As a result, this method is
infrequently used.
Another
method,
amniography,
or
X-ray examination of the fetus, 29 is useful for finding disorders that are characterized by the absence, or gross structural abnormality,
of specific bones.~
One such example is achondroplasia,
a
type of dwarfism, which can be recognized radiologically
at between 20 and
24 weeks of pregnancy. 19
Finally, a relatively new method of
diagnosing neural tube defects, a class
of malformations
of the brain and spinal
cord including anencephaly
and spins
bifida, is the alpha-fetoprotein
(AFP)
test.31 Neural tube defects, which can
lead to death, paralysis,
and mental
retardation
and occur somewhat randomly, can be prenatally detected by
analyzing the mother’s blood serum for
levels of alpha-fetoprotein.
This protein
normally rises in concentration
in the
mother’s
serum
during
pregnancy.
Higher than normal quantities may indicate the presence of a neural tube
defect, multiple pregnancy, fetal death,
or other defects. When found, this indicates a need for additional tests. Kits
for this test, which could be used for
widespread screening, are currently being evaluated by the US Food and Drug
Administration.Q
Incidentally,
the
primordial
publication
on the AFP
testsl was recently a Citation Chrsic. 33
most diagnostic
tests
Of course,
reveal that the fetus is normal, which
can relieve parents of the anxiety they
may have from suspecting it is defective. When a defective fetus is detected,
this knowledge—besides
giving parents
the choice of abortion-enables
the
physician to begin treatment
at birth
and, in some cases, treat the fetus in the
womb.
Many of these diagnostic tests are
used
in conjunction
with
genetic
counseling. As defined by C.R. Striver,
McGill University, genetic counseling is
“a communication
process that attempts
to help an individual or family to comprehend medicaf facts, to appreciate
how heredhy contributes
to the dkorder, to understand the options for dealing with recurrence
risks, to act upon
these options in a manner appropriate
for the counselee, and to make the best
possible adjustment to the presence or
risk of the disorder in themselves, their
offspring or other family members. ” 1I
The genetic counselor generally performs a complete medical review of the
individual’s pedigree, or family tree. If
there’s a possibilhy that the parents are
carriers
of a hereditary
disease or
deleterious genes, they are advised of all
options, including predictive tests when
possible. In many instances,
genetic
counselig
involves more than the purely scientific prediction of recurrence of
hereditary disease. It may include helping the parents examine their attitudes
toward having a defective child. Genetic counselors may afso provide information about the financial and emotional
aspects of raisiig such a chiid, and help
parents who already have a defective
child cope with their situation,
Most of this counseling had been
done in the past by doctoral
level
geneticists.
More recently,
internists,
pediatricians,
and obstetricians
with
special knowledge of medical genetics
have offered genetic counseling. And at
least eight universities now offer programs leading
to either
a master’s
degree
in genetic
counseling
or a
master’s in social work, with a genetic
counseling
specialt y.s These include
Sarah Lawrence College; University of
California
at Berkeley,
Los Angeles,
and Irvine; Howard University; Universit y of Michigan School of Medicine;
University of Pittsburgh; and University
3
of Wisconsin-Madison.
No US certification has been offered
in this area in the past, but in December, the recently established American
Board of Medical Genetics will offer
certification through a series of five examinations. These exams, which will be
administered
by the National Board of
Medical Examiners, will include a core
exam to be taken by all medical geneticists, a clinical geneticist exam to be
taken by physicians
and dentists,
a
medical geneticist
exam for persons
with doctorates,
a clinicaf biochemical
geneticist exam, a cliiical cytogeneticist
exam, and an exam for genetic counselors. Hope Punnett,
a member of the
American Board of Medical Genetics,
said the board hopes to offer an exam in
ctilcal immunogenetics
in the future. ~
The Canadian College of Medical Geneticists,
which was incorporated
in
1975, has been certifying MD and PhD
medical geneticists for several years, 1I
Most people who consult genetic
counselors do so after already having
had a child with a hereditary disease.
Others are patients with a history of
genetic disease they don’t want to pass
on.JS But many physicians advocate the
use of genetic counseling prior to marriage, Even simple knowledge about Rh
factors needs to be explained. In emphasizing the preventive nature of medical genetics, A. Mdunsky, Harvard University, lists such options as careful
selectibn of a mate, determining if you
are a carrier, prenatal testing, abortion
of severely defective fetuses, artificial
insemination,
and adoption.
He also
226
recommends
that individuals who suspect they are earners of a genetic disease be screened for the dkease in question.~
Population
screening for carriers of
genetic diseases has been successfully
applied to Tay-Sachs disease, an enzyme deficiency carried by one in 30 US
Jews of Ashkenazic (East European) descent, and, to a lesser extent, to sickle
cell anemia, a blood dkease earned by
one in ten Black Americans. Screening
for thalassemia has been done in several
Mediterranean
countries and in parts of
the US.~ Since genes for these diseases
occur more frequently in these subpopulations, and fairly accurate tests are
available for their detection,
a widespread screening program can be costeffective. But most genetic diseases occur less frequently in larger populations,
so the costs of routine
population
screening for those few d~eases which
can be detected are less cost-effective.
Hereditary diseases can be passed on
to progeny in a variety of ways. Most
diseases are recessive, which means that
a person must inherit a defective gene
from both parents in order to manifest
the d~ase associated with that gene. If
both parents are earners of the same
gene, each chfid will have a 50 percent
chance of being a carrier (carries the
gene but does not have the dkease). For
each child there is also a 25 percent
chance of having the d~ease and a 25
percent chance of not being a Carner or
having the disease. Most forms of albinism, which affects the pigmentation of
the skin, hair, and/or eyes, are recessive.~
With dominantly inhetited diseases,
at least one parent has a gene that
dominates the counterpart,
or “allele,”
contributed by the other parent. In this
case, each child of an affected individual has a 50 percent risk of inheriting the
disease. Certain dominantly
inherited
diseases may be expressed more severely in one member of a family than in another. One such example is neurofibro227
matosis, a chsorder of the brain and nervous system in which some children may
have mild and others severe symptoms.
Over 100 hereditary
diseases
are
known to be X-linked. These disorders
result from a defective gene on one of
the X chromosomes. In X-linked inhentance, each of a female earner’s sons
will have a 50 percent chance of inheriting the X-liiked
d~ease,
and each
daughter, a 50 percent chance of being
a carrier. If only the father has the
disease, the daughters wilf alf be carriers
and the sons will not be affected. Finally, if the father has an X-linked disease
and the mother is a carrier, there is a 50
percent chance a daughter will be affected and a 50 percent chance she wiff
be a carrier. There is also a 50 percent
chance a son will be affected.
Many
forms of mental retardation are believed
to be X-linked.~
Most X+mked genetic defects cause
overt disease only in sons. Daughters receive two X chromosomes,
which may
counteract each other, but sons receive
only one X, and a Y which does not
counteract
the genetic disease carried
by the X. So determining that a fetus is
male is often the only way to find out if
the mother is likely to have an affected
chdd. For example, if the mother is a
carrier of the hemophilia gene, which
causes d~ease only in males, each of her
male children wilf have a 50 percent
chance of having the disease. Unf ortunately,
only six X-linked diseases—
Hunter
syndrome,
Fabry’s
disease,
Lesch-Nyhan
syndrome,
Menkes syndrome, several forms of hemophilia,
and chronic granulomatous
dwasecan actually be detected in the fetus
itseff. So mothers who are carriers of
other severely debilitating
hereditary
disease genes may choose to abort all
male fetuses.~ This was formerly done,
on occasion, with hemophilia, but new
methods of therapy are improving the
prognosis in this disease and selective
abortion of males is becoming questionable. Since there is no adequate ther-
spy, carriers of certain types of muscular dystrophy genes sometimes elect to
abort all male fetuses.
While some carriers
of X-linked
diseases may have mild manifestations
of the dkease, there may be some advantage to being a earner, particularly
of a recessive dkease.
In some instances, carriers may have increased
resistance to an unrelated disease. For
example,
carriers
of the sickle cell
anemia gene have greater resistance to
malaria. ~ %nilarly,
individuals
with
Duffy
negative
blood
group
have
greater resistance to a certain type of
malaria. 37
There are three basic types of genetic
disease.
In Mendelian
inheritance,
which I discussed above, single genes or
gene mutations are inherited in recogThis accounts
for
nizable patterns.
about 25 percent of genetic disease.
Chromosomal aberrations, or an abnormal number of chromosomes caused by
mutation
or inheritance,
account for
about 13 percent, and multifactorial
or
polygenic inheritance,
in which the interaction of genes and nongenetic (environmental)
factors cause disease, accounts for about 44 percent. %
Despite the fact that about four percent of aU livebom children will have
some hereditary
disorder, zd there are
only about 231 genetic counseling and
screening programs in the US3 and 843
worldwide. BQThe lack of insurance payment for genetic counseling has prob
ably been a factor in the paucity of programs. In fact, at least one study
showed that the majority of patients
who come for counseling are in the middle and upper income brackets.gs
When you consider that it costs at
least $250,000 for lifetime support of a
person with Down syndrome,~
the
justification for insurance payment for
these services becomes evident. Milunsky emphasizes the price paid by parents who have not availed themselves of
genetic services. “The presence of a
chdd with serious birth defects in the
228
home becomes a chrome emotional ana
physical drain on the parents, leading
often to a severe state of exhaustion affecting all avenues of their life. Economic hardship may follow and ahnost
invariably increases marital conflict . . . .
Separations
and divorce are only too
well known in farnihes where such
tragedies have occurred. The enormous
drain on the energies of the parents frequently leads to a relative neglect of the
unaffected children. ”m (p. 9)
Although the emphasis of medical genetics has been largely on birth defects
and prenatal screening,
this is by no
means the only field in which an understanding of the genetic basis of disease
has been applied.
As I mentioned
members
of the biomedical
earlier,
community
are investigating
and, in
some cases, applying their knowledge of
genetics
to hereditary
diseases that
manifest themselves later in Me.
While research on the genetic basis
for such dkeases is still fairly new, investigators are beginning to emphasize the
individuality
of each person’s genetic
profile.
Striver
and colleagues,
in
discussing
the evolution
of medical
genetics,
explain
that
the genetic
paradigm for disease “recognizes
the
role of intrinsic (genetic) factors for individual homeostasis and susceptibility
or resistance to disease . . . . Because individuals
have
genetic
their
own
signature,
it follows from the genetic
paradigm that each person is at his or
her own specific risk for a particular
disease.”11
Coronary heart disease, for example,
is often associated
with high blood
levels
of cholesterol
or triglyceride—conditions
which
are partially
determined
by genetic factors.
One
such condition, familial hypercholesterolemia, is transmitted through a dominant form of inheritance.
It can be
treated through reductions in the intake
of cholesterol
and saturated fat. The
gene for this disease is carried by about
one in every 500 individuals in the US. -~
Another
disease,
familial hypertriglyceridenda, affects about one in every
300 individuals in the US. In addition to
coronary
disease,
individuals
with
familial hypertriglyceridemia
have a
higher frequency of diabetes and obesity, and may be resistant to insulin.m
In familial combined hyperlipidemia,
which affects nearly one in 200 in the
US, there is a high blood fat level that
can cause heredhary disease. Finally, in
polygenic
hypercholesterolemia,
high
blood cholesterol is caused by the interaction of genes and environmental
factors. Other genetically related causes of
heart disease include hereditary defects
in the structure of the heart and hypertension.~
There is also evidence that cancer
may have a hereditary component.
For
example, it has been found that women
with breast cancer that occurs prior to
menopause
often have affected relatives, particularly when the cancer occurs in both breasts. It has been suggested that some susceptible
women
lack an enzyme (estradiol hydroxylase)
that would normally process the estrogen made by their ovanes.m Specific
cancers have also been associated with a
number of chromosomal
disorders, including Down syndrome and Klinefelter
syndrome,~
Addhionally, it is currently
believed that many malignant disorders
occur in genetically disposed individuals
exposed to environmental
carcinogens.
A review article by Purtilo and colleagues lists more than 240 tumors that
may have a hereditary component, 40
Studies to assess the genetic components of disease often involve comparing the behavior and disease patterns
of identical and nonidentical twins.dl 42
Since identical, or monozygotic,
twins
have identical genetic profiles, a high
concordance
rate bet ween them, as
compared to dizygotic twins or siblings,
suggests a genetic basis for the condition being considered. Researchers also
conduct studies on adopted children in
an effort to isolate the environmental
229
Iactors that might contnbute to disease.
If a relationship can be made between
the illness of biological parents and the
child they’ve given up for adoption,
genetic factors may be implicated.
In his review of genetic counseling for
psychiatric
patients,
M.T.
Tsuang,
University
of Iowa, reports
that in
severe alcohol abuse a concordance
rate of 84.5 percent was found between
identical twins, while the rate was 66.7
percent for fraternal twins.ds He also
notes that a Danish study of alcoholism
among adoptees and their parents found
a much higher rate of alcoholism in the
sons who had been adopted from alcoholic biological fathers than among control adoptees. The rate was no higher
for daughters who had been adopted
from alcoholic fathers.
A number of other psychiatric disorders,
including
manic-depression, 44
schizophrenia, and presenile dementia,ds
also are believed to have a genetic component. George Winokur, University of
Iowa, is among many scientists who
believe that bipolar, or manic-depressive, illness can be genetically transmitted. He afso suggests there is a genetic
component in unipolar, or depressive, illness. Winokur estimates that the sibfing
of a manicdepressive
individual has a 26
percent risk of being affected if one
parent is affected, and a 43 percent risk if
both parents are affected.~
Not surprisingly,
“ecogenetic”
studies—studies of genetic variation in susceptibility
to physical, chemical,
and
biological
environmental
agents—are
increasing as new knowledge of genetics
becomes available. 47 These studies are
concerned with many of the genetic diseases I’ve already discussed, particularly
those that can be considered muhifactorial.
Many types of cancer are suspected
of being ecogenetic, since specific cancers occur more frequently in certain
geographic areas. Researchers
are exploring the possibility that “genetically
determined differences in carcinogenic-
.,
ation, ~ are known to cause genetic mutations Ieadmg to disease, reduced fertilhy, and the birth of defective children. Researchers
at several institutions, including the University of British
Columbia, the Chalk River Nuclear Laboratories, Ontario, 51 and the University
of Oslo, 52 are looking at how these mutated genes are carried by future generations, and at the repair mechanisms of
these genes.
The diseases that may be environmentally induced as a result of genetic
predisposition
are too numerous
to
name here. However, a review of these
diseases makes it eminently clear that
many political and social problems will
arise before a fulf understanding
of
genetically determined disease has been
reached, Indkiduals
susceptible to any
of the diseases that can be provoked by
exposure to chemical substances may be
barred
from jobs employing
these
chemicals. Food additives known to induce disease in predisposed individuals
may have to be taken off the market.
Controversies
and problems
have
already surfaced from what is known (or
not known)
about
susceptibility
to
disease and about people who are carriers of harrnf ul recessive genes. In the
US, several Black people were barred
from the armed forces and asked to pay
higher insurance
premiums
because
they carried the sickle cell anemia gene.
And in Greece, young women discovered to be carriers of thk trait found
themselves
ineligible for prearranged
marriages. ~
Even more volatile arguments
are
currently under way concerning prenatal
diagnosis,
abortion,
and genetic research. Questions arise about the right
to life of the defective fetus independent of the lifetime burden the handicapped child will be for its parents and
society. Several authors have suggested
that illnesses that are prenatally diagnosable but can’t be treated at present
may be ignored by medical researchers.
These authors imply that, since fetuses
metabolizing enzymes affects susceptibility to various cancers. ‘“@Lactose intolerance~
is thought to be a recessive
ecogenetic
dkease,
while the factors
that determine whether or not caffeine
will keep you awake at night may be
genetically determined.~
A subfield of ecogenetics, pharmacogenetics, is concerned with hereditary
factors that affect individual reactions
to drugs and chemicals, Pharmacogeneticists emphasize the need to investigate each patient’s genetic susceptibility
to various drugs before they are administered and to tailor drug regimens
to individual needs. Many hereditary
condhions, which by themselves cause
few problems, are activated when the
affected individual is exposed to various
drugs. A classic example is glucose-6phosphate
dehydrogenase
deficiency,
an inherited deficiency of an enzyme
within the red blood cell. This disorder
occurs most often among Orientals and
Blacks. If a person with this deficiency
takes any of a number of drugs, includlng aspirin, he or she may develop a
hemolytic anemia, a condition in which
red blood cells are destroyed.~
Alcoholism
is also the subject of
pharmacogenetic
investigation.
For example, Peter Propping,
University of
Heidelberg,
suggests that genetic factors may influence an individual’s ability
to metabolize alcohol, as well as his or
her tolerance of, and dependence
on,
this substance.
A number of observations support a genetic basis for susceptibility to alcoholism.
They include
varying EEG patterns following alcohol
consumption
and differing enzymatic
reactions
to alcohol
among various
populations. Mongolian people, for example, respond to alcohol with rapid,
intense flushing of the face and symptoms of intoxication
much faster than
do most Caucasians. @
Exposure of genetically disposed individuals to various chemicals is believed
to cause cancer and other diseases. A
number of chemicals, and ionizing radi230
with these defects can be detected and
aborted, researchers wiff feel there is no
need to search for cures.
As Joshua
Lederberg,
president,
Rockefeller
University,
points
out,
“Few subjects pose as many difficulties
for rational discussion as does the bearing of genetic research on human welfare. It is monotonously
coupled with
such inflammatory
themes as racism,
the decline of the species, overpopulation, hidden genocide, religious debates
on abortion
and contraception,
the
plight of the individual in mass society,
and ‘how many generations of idiots is
enough?’ “~~
Graham Chedd, in a recent issue of
Science 81, examines
many of the
ethical implications of genetic screening. “There is also the fear that abortion
for genetic
disease could gradually
evolve from being the ‘responsible’ to
being the ‘expected’ thing to do,” he
writes. “Proponents of genetic abortion
argue that knowing a fetus is defective
increases the prospective parents’ freedom of choice . . . . But seeing the benefits to society of mandato~
abortion
isn’t difficult. Perhaps the deepest apprehensions
about the use of genetic
abortion stem from the ever-increasing
range of prenatal diagnosis. If we see it
as acceptable,
even responsible,
to
abort now for Down’s syndrome, what
will be the attitude in the future when,
say, muscular dystrophy can be diagnosed prenatally?”%
A number of legal questions have also
been raised about the physician’s obligation to provide genetic counseling and
inform patients about prenatal diagnostic tests currently
available.
Several
‘“wrongful life” lawsuits
have been
brought against physicians by parents
and children because of the doctors’
failure
“to detect
or disclose
the
possibility that a defective child will be
bO~.
”55
Despite these questions, the value of
genetic screening has been recognized
by many governments,
as well as re231
searchers and physicians. In 1976, the
US Congress passed the National Genetic Diseases Act which provides for a national program of information and education
in connection
with genetic
diseases. 56 A National Clearinghouse
for Human Genetic Disease has been
established under this act, and funding
has been provided to the states for
genetic services.J In Canada, which has
a universal health insurance program,
the government afso sponsors resources
for the screening, diagnosis, counseling,
and treatment of heredhary disease. 11
The Clinical Genetics Society in the UK
recently prepared a report outlining the
training requirements
and functions of
the medical geneticist .57
Although the preventive implications
of this field are recognized, there is still
some resistance to the incorporation
of
human genetics into medical practice.
Barton Chdds, Johns Hopkins University, reports that few physicians surveyed
in 1975 considered
genetic disease a
serious practical problem.~
As I mentioned in the preventive medicine essay,
physicians
are more concerned
with
“curing” patients of specific diseases
than with preventing
future
illness.
Childs also cites the physician’s concern
with indkidual
patients,
rather than
families, and the episodic nature of
medical treatment,
as factors precluding the application of med]cal genetics
to standard medical practice. In a fater
article, he points out that medical genetics is usuafly a minor part of the
medical school curriculum, and is often
not clinically-oriented.
59
With more research on human genetics will come greater recognition of the
preventive,
or “predictive,”
value of
medical genetics. Already, researchers
are finding ways to track the inheritance
of genetic disease through differences in
the DNA at specific regions of the chromosome, calfed DNA polymorphisms.
David Botstein,
MIT, and Raymond
White, University of Utah, are tracing
the inheritance
of these
markers
through several generations, and investigating the relationships between these
markers and specific genetic diseases. ~
Currently,
other “markers,”
or traits
carried by a gene on the same chromosome that carries the gene for a genetic
disease, are used to trace inherited disease in families. These include blood
group, color bliidness,
serum protein
polymorphisms,
the ability to taste
phenylthiocarbamide,
and HLA antigens.
Associations
have been made between HLA antigens and such diseases
as rheumatism,
ankylosing spondylitis,
arthritis, psoriasis, asthma, and Hodgkin’s disease.bl.bz There may also be an
association between these antigens and
juvenile onset diabetes and myasthenia
gravis.61 Unfortunately,
blood tests for
these antigens are fairly expensive and
difficult. Scientists are also mapping the
locations of genes on chromosomes,
and investigating
transplantation
and
replacement of defective genes.b$~ According to McKusick, “We now know
the speciiic chromosome
canying each
of over 450 human genes and the specific localization
of that chromosome
is
known for many of these. For some
segments of the DNA the anatomy is
known now down to the individual
nucleic acids. ”lQ
Medicaf genetics is a field that frequently interfaces with other areas of
biomedical
research.
Several of the
highly active specialties
in ISI/BIOMED ‘“ that deal directly with medical
genetics touch upon many of the diseases and research areas I’ve mentioned
here (see Table 1). For example, we
have one research front that deals exclusively
with
genetic
aspects
of
alcoholism, and several that deal with
genetic aspects of cancer and other
diseases.
Among the many co-citation clusters
produced from our data base, there are
several which focus on genetic diseases
caused by enzymatic deficiencies. The
work of McKusick
and colleagues is
particularly relevant to thk essay and to
these chssters.bS-bT McKusick, who will
appear on our forthcoming list of 1,003
most-cited
authors,
is probably
best
known for his catalog
of genetic
diseases~ and was one of the earliest
clinicians to promote an understanding
of the role of genetics in human disease.
The entries for this catalog, which was
first published in 1966, are kept in a
computer fide that is continuously
updated. A recent count, in June, revealed
that about 3,254 genetic loci have been
identified,
half of which “were quite
clearly identified as real and distinct, ”
and haff of which were tentatively
“identified and included for heuristic
purposes and none other. “19
The growth of this field is also
evidenced by the presence of medical
genetics papers in a wide range of journals, inchsdmg Lancet, Journal of the
Amen”can Medical Association, American Journal of Psychiatry, and New
England Journal of Medicine. A number of the popular science magazines
also
publish
articles
on
medical
genetics.
The
major
sources
of journal
literature on the subject are the American Jouma[ of Human Genetics, Amen”can Journal of Medical Genetics, Annals of Human Genetics, Human Genetics, Journal of Medical Genetics,
and Clinical Genetics. All are covered
by the
Science
Citation Indexa,
ASCAm, and Current Contents@ /Life
Sciences. The Amen”can Journal of
Medical Genetics, Clinical Genetics,
and Journal of Medical Genetics are
also covered in Current Contents/Clinical Practice. These, and several other
joumafs that publish papers related to
medical genetics, are presented in Table
2 along with the number of articles
published in 1980; the number of citations received
in 1980 by articles
published in these journals; their impact
factor, a measure of the frequency with
which the average 1978/ 1979 article has
been cited in 1980; and their immediacy
232
TabEe 1: Some of the genetic d~ease research front specialties identfited by co-citation analysis
in ISI/BIOMED ~U
GENETIC
GENETICS
BACTERIOPHAGE.LAMBOA
GENETIC
The AH-LOCUS ●nd GENETIC control of
19800258
CARCINOGEN METABOLISM
GENETICS
COLLAGEN }ynthesn ●nd GENETIC
I 9800479
POLYMORPHISM
ENvIRONMENTAL
CttEMlCAL5
ca@mg CANCER
1980 1204
and GENETIC BIRTH OEFECTS
EVOLUTION ●nd GENETIC VARIABILITY
lQRfl
1R72
. . -----
GENETIC and ENVIRONMENTAL
etfects on DRUG
1980 1868
METABOLISM
19801506
GENETIC q)ecfs
of ‘ALCOHOLISM
GENETIC control ot CELL-MEDIATED
IMMUNE
19802087
RESPONSIVENESS
GENETIC c~kd
of COMPLiMENi
‘+FYOTEIN
structure bv the HISTIXOMPATIBILITY
19800100
Cmpw
.“
GENETlc control Oi tYTtii+’ROhiEp-450
19800258
GENETIC control of HYDROXYIASE
xtw!
IQ P (ll&<7
HYPERCHOLESTEROLEMIA
RISK. ASSESSMENT of FAMILIAL
HYPERCHOLESTERDLEMIA
and
HYPERLIPIDEMIA
19800342
m HYBRID
1980 1787
1980 1936
DIET ●nd HYPERLIPIDEMIA
RISK ASSESSMENT
of FAMILIAL
MYPERCHOLESTEROLEMIA
and
HYPERLIPYDEMIA
19800684
PURINE synthe$ts, HPRT def!cwncy,
NYHAN SYNDROME
)640
19802258
●nd LESCH
!980 1937
M(JSLXJL4R.D YSTROPHY
CYTOPATHOLOGY ●nd PATHOPHYSIOLOGY
of
19802030
MUSCULAR DYSTROPHY
ERYYHRDCWE
PUStAA+4EW3RANi
ABNORMALITIES
m DUCHENNE MUSCLJLA R
198017)4
DYSTROPNY
S/CflLE-CELL
GELATION
of SICKLE CELL HEMOGLOBIN
19801690
T)iAIASSEMIA
IRON CHELATION THERAPY for THAIASSEMIA
and oftw c!+rwalsfate8 produang IRON
OVERLOAD
1980.0369
. .. .
TtiAUSSEMIAS
GENETIC.LINKAGE
MOLECULAR
GENETICS
●lUtyUL for RECESSIVE
19801243
of THALASSEMIA
198 8 .0271
lJLTRASOFVLXRAPWC
GENETICALLY
of GENETICALLY
1980
LESCH.NYHAN-S YNl?ffOME
. -------
PHYSIOLOGY
19802258
lfYPERLiPfOEMIA
19800616
1980 1033
GENETIC vanatma
GENETIC DETERMINANTS
of remitkc
to
ANTIBIOTICS b NEISSERIA.GONORRHOEAE
i
1980-0240
andofher BACERIA
. . . . . . .
GENETIC MAPPING of HEAT-SHOCK INDUCIBLE.
GENES m DROSOPffltAMEMNDGA
TER
1 ? 80 1653
GENETIC POLYMORPHISM
m FINITE
..,. - ,. .-. -.,1980 1616
—Ullvn>
GENETIC POLVMC )Rbitishi “Of iitiHROcYTE
FU7VUF(s
19801317
SEQUENCES
GENETIC RE5CIXNITION “and’ crkol
19802273
m the NUCLEIC-ACIDS b.. .
GENETIC RECOMBINATION IN of ON”CDGENIC
19800325
VIRUSES
GENETIC REsTRicTto”fi Of kiACROpNAGE T.CELL
1980 1261
mtemctmrm
GENETIC, ENVIROtiMEN”TAL, and t.iIkTARY
confnbubons to CHILDHOOO ●nd
ADOLESCENT GROWTH dynam,cs
1980. ?79?
MODELS of GENETIC control of ENZYME actw
198021 ? 0
GENETIC-LINKAGE
dmeasu
●-d HYPERCHOLESTEROLEMIA
19800B59
NuTRITION
COftfd of T-CELL SPECIFICITY
GENETIC confrd of TUMORIGENICITY
CELLS.
GENETIC ●tfecfs ot DYES M’ ONA
GENETIC w ●mzafmn of NEMATOOE
CAENOR%ABDITIS. ELEGANS
GENETIC studw of AGRO~ACTERIUM
19800040
1980.0917
GENETICS of BACTERIAL RNA-POLYMERA
ES
198 8 .1841
MOLECULAR GENETICS of human HEM
,%%’?,
MOLECULAR GENETICS of FETAL HEM
1$%%?
1
MOLECULAR GENETICS of MITOCHONDRIAL
DNA
1980.063
?
MOLECULAR GENETICS Ot TiALASiEMIA
198
0271
‘wMT’ON
‘ENET’CS
0’ “O’w!l%no
TERATIXARCINOMA
TRANSPLANTATION
STEM
CELL GENETICS ●nd IMMUNO.REJECTION
19800232
LOCI
--------
GENETIC
GENETICS
of mouse LELJKEMIA.VIRUS
ULTRASONDGRAPHIC
meawrement
GESTATIONAL AGE
OBESE m,ce
19800681
of
19800823
index, a measure of how quickly
.
. the I tioned before, a National Clearinghouse
for Human Genetic Dkease has b~en esaverage article published in 1980 was
tablished under the National Genetic
cited.
Diseases Act. This clearinghouse,
which
Several computerized
data bases are
can be contacted
at P.O. Box 28612,
currently
being developed,
including
Washington,
DC 20005, provides infortwo at Columbia Universit@f and the
mation on genetic screening and treatUniversity of California at San Franment programs.
An annual course in
cisco,~
that are expected
to serve
medical
genetics
and
experimental
research,
service, and administrative
mammalian
genetics is offered jointly
needs in medical genetics. As I men-
233
Table 2: Selec!ed list of medical genetics journals ccwered by Currenf C’[email protected]’ and the
Science Cifar,on Indexz, wit b the total number of articles they published in 1980, the total
number of citations they received in 19S0, their impact factor, and [heir immediacy index.
Source: 1980 SCP Joumoi Cmzzmn Repotis’>’
1980
Artkles
Pubfkhed
5
89
108
33
63
43
53
136
131
51
229
85
71
223
73
48
2-?
44
110
109
I20
Advances in Human Genetics
American Journal of Human Genetics
American Journal of Medical Genetics
Annals of Human Genetics
Annales de Genetique
Behavior Genetics
Canadian Journal of Genetic Cytology
Clinical Genetics
Clinical Pediatrics
Genetical Research
Genetika
Hereditas
Heredity
Human Genetics
Human Heredity
Japanese Journal of Genetics
Japanese Journal of Human Genetics
Journal de Genetique Humaine
Journal of Heredity
Journal of Medical Genetics
Tk.sue Antigens
1980
Total
Chatiom
Impact
Factor
Immcdkcy
Index
122
2431
206
1334
679
443
884
1340
802
1133
955
1810
I573
2254
594
452
145
156
1438
1304
I4s3
,429
3.643
.944
1.602
1.375
I .594
1,024
1.566
.478
I .070
.372
1.701
1.309
1.7b3
,894
.828
.774
.400
,694
1.221
1.657
.MX1
.382
.139
.697
.095
.256
.208
.169
.031
,294
.240
.329
.394
.318
.137
.292
.222
.091
,{27
,183
.233
I
by Johns Hopkins University and Jack- I North Carolina 27709, or the Genetics
son Laboratory. For information on this
Society of Canada, through its presicourse, which has been offered since
dent, R.C. Von Borstel, University of
1960, contact Victor McKusick, Johns
Alberta, Department
of Genetics, Edmonton,
Alberta T6G 2E 1, Canada.
Hopkins Hospital, Baltimore, Maryland
The International
Genetics Federation,
21205, or Thomas H. Roderick, Jackson
P.O. Box 1600, Canberra 2601, AustraLaboratory, Bar Harbor, Maine 04609.
lia, is comprised of societies concerned
A number of organizations
exist for
with both human genetics and plant
professional geneticists and individuals
interested
in, or affected by, genetic
breeding,
and the Behavior Genetics
Association,
which can be contacted
dkease. The American Society of Huthrough
the Institute
for Behavioral
man Genetics, c/o Judith Brown, SecreGenetics,
University
tary, Box 33 MCV Station, Richmond,
of Colorado,
Virginia 23298, is a professional society
Boulder, Colorado 80309, is a professional
organization
for
individuals
of physicians,
researchers,
teachers,
genetic counselors,
and others in the
engaged in teaching or research in some
field. The American Genetic Associaarea of behavior genetics. The National
tion, 818 18th Street, NW, Room 250,
Genetics Foundation,
555 West 57th
Washington, DC 2C@6, includes bioloStreet, New York, New York lCOl 9,
gists, zoologists, geneticists,
botanists,
conducts educational programs for the
and others in academic or government
public and physicians and operates a
research. Individuals interested in any
network of genetic counseling and treatfield of genetics
can contact
the
ment centers. The National Society of
Genetics Society of America, through
Genetic Counselors can be contacted
its president, Burke Judd, NIEHS, P.O.
through Beverly Rollnick, Center for
Box 12233, Research
Triangle Park,
Cranialfacial
Abnormalities,
University
234
of Illinois, Abraham Lincoln Center,
470-DMP, P.O. Box 6998, Chicago, 11Iinois 6068Ll. The international
Society
for Twin Studies can be contacted at the
Mendel
Institute,
Piazza Galeno
5,
00161 Rome, Italy, and the Association
for Research
into Restricted
Growth
can be contacted through Valerie Sims,
Secretary,
5 Peak
Walk,
Witham,
Essex, England.
There are also a number of voluntary
organizations
concerned
with hereditary diseases. Included among these are
the Hereditary
Disease
Foundation,
9701 Wifshire Boulevard, Beverly Hills,
California 902 12; the March of Dimes
Birth Defects Foundation,
1275 Mamaroneck Avenue, White Plains, New York
10605; National Tay-Sachs and Allied
Diseases Association,
122 East 42nd
Street, New York, New York 1(X)17;
Cooley’s Anemia Foundation,
420 Lexington Avenue, Suite 1644, New York,
New York 10019; Cystic Fibrosis Foundation,
3379 Peachtree
Road,
NE,
Atlanta, Georgia 30326; National Association for Down’s Syndrome, Fullerton
Avenue,
Addison,
Iflkois 60101; National Foundation
for Jewish Genetic
Diseases, Inc., 609 Fifth Avenue, Suite
1200, New York, New York lCN)l7; National
Association
for Sickle
Cell
Diseases,
Inc., 3460 Wilshire Boulevard, Suite 302, Los Angeles, California
90010; National Hemophilia
Foundation, 25 West 39th Street, New York,
New York 10018; National Huntington’s
Disease Association,
128A East 74th
Street, New York, New York 10020;
Spina Bifida Association
of America,
343 Dearborn Avenue, Room 319, Chicago, Illinois 60604; Parents Helping
Parents,
47 Maro Drive, San Jose,
California 95127; and Little People of
America,
P.O. Box 633, San Bruno,
California 94066. Associations
outside
the US include Little People’s Association of Australia,
c/o Robert Wood,
10/ 16 Roslyn Gardens, Elizabeth Bay,
NSW 2011, Australia; Les Petits Tailles,
c/o Claude Stoll, Institut de Puericulture, Hospices Civils, 6730 Strasbourg,
France; World Federation of Hemophilia, 1170 Peel Street, Suite 1126, Montreal, Quebec H3H 2J 1, Canada; and
Association
for Research
into Restricted Growth, c/o Mary Lindley, 2
Mount Court, 81 Central Hill, London
SE19 lBS, England.
Medical genetics is making inroads
into standard medical practice.
Blood
tests given adults are regularly screened
for the presence of genetically
influenced high cholesterol and triglyceride
levels. Obstetricians
are advising older
pregnant
women to take diagnostic
tests. As McKusick pointed out in a recent letter, “ . . man is rapidly becoming
the best studied of the mammals from
the genetic point of view..., The big advantage that man has as an object of
genetic study is, of course, the anthropocentric
interest in our own species
and the fact that we have such a large
segment of the world’s population working for us, in effect, cofIecting information on human variation from an anaphysiologic,
pathologic
and
tomic,
biochemical point of view.”lg However,
before all this information can be used
to fully benefit human health, a great
deal of research must stilf be done on
the detection, hereditary patterns, and
treatment of genetic diseases, and easily
administered,
inexpensive tests must be
developed to fmd them.
●
****
My thanks to Joan Lipinsky Cochmn
and Patn”cia Heiler for their help in the
prepamtion of this essay.
OW ,s$
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